RTEL1 Regulates G4/R-Loops to Avert Replication-Transcription Collisions.

Regulator of telomere length 1 (RTEL1) is an essential helicase that maintains telomere integrity and facilitates DNA replication. The source of replication stress in Rtel1-deficient cells remains unclear. Here, we report that loss of RTEL1 confers extensive transcriptional changes independent of its roles at telomeres.

CDK phosphorylation of TRF2 controls t-loop dynamics during the cell cycle.

The protection of telomere ends by the shelterin complex prevents DNA damage signalling and promiscuous repair at chromosome ends. Evidence suggests that the 3' single-stranded telomere end can assemble into a lasso-like t-loop configuration, which has been proposed to safeguard chromosome ends from being recognized as DNA double-strand breaks. Mechanisms must also exist to transiently disassemble t-loops to allow accurate telomere replication and to permit telomerase access to the 3' end to solve the end-replication problem.

IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer.

Phosphorylated IKKα(p45) is a nuclear active form of the IKKα kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-κB signaling. Insights into the sources of IKKα(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKα(p45) is rapidly activated by DNA damage independent of ATM-ATR, but dependent on BRAF-TAK1-p38-MAPK, and is required for robust ATM activation and efficient DNA repair.

IKKα is required in the intestinal epithelial cells for tumour stemness.

Background: Colorectal cancer is a common cause of death in developed countries. Progression from adenoma to invasive carcinoma requires accumulation of mutations starting with the Adenomatous Polyposis Coli (Apc) gene. NF-κB signalling is a key element in cancer, mainly related to the activity of IKKβ.

Stabilization of Reversed Replication Forks by Telomerase Drives Telomere Catastrophe.

Telomere maintenance critically depends on the distinct activities of telomerase, which adds telomeric repeats to solve the end replication problem, and RTEL1, which dismantles DNA secondary structures at telomeres to facilitate replisome progression. Here, we establish that reversed replication forks are a pathological substrate for telomerase and the source of telomere catastrophe in Rtel1 cells. Inhibiting telomerase recruitment to telomeres, but not its activity, or blocking replication fork reversal through PARP1 inhibition or depleting UBC13 or ZRANB3 prevents the rapid accumulation of dysfunctional telomeres in RTEL1-deficient cells.

Molecular basis of telomere dysfunction in human genetic diseases.

Mutations in genes encoding proteins required for telomere structure, replication, repair and length maintenance are associated with several debilitating human genetic disorders. These complex telomere biology disorders (TBDs) give rise to critically short telomeres that affect the homeostasis of multiple organs. Furthermore, genome instability is often a hallmark of telomere syndromes, which are associated with increased cancer risk.

Active nuclear IKK correlates with metastatic risk in cutaneous squamous cell carcinoma.

About 5% of all cutaneous squamous cell carcinomas (cSCCs) metastasize, which is the principal cause of death by this type of cancer. However, to date there are no reliable biomarkers that categorize those SCC patients that will progress to metastasis. Nuclear active IKKα diminishes Maspin levels in prostate cancer facilitating its metastatic potential.

BRAF-induced tumorigenesis is IKKα-dependent but NF-κB-independent.

KRAS mutations contribute to cell proliferation and survival in numerous cancers, including colorectal cancers (CRC). One pathway through which mutant KRAS acts is an inflammatory pathway that involves the kinase IKK and activates the transcription factor NF-κB. BRAF, a kinase that is downstream of KRAS, is mutated in a subset of CRC and is predictive of poor prognosis and therapeutic resistance.

Chromatin-bound IκBα regulates a subset of polycomb target genes in differentiation and cancer.

IκB proteins are the primary inhibitors of NF-κB. Here, we demonstrate that sumoylated and phosphorylated IκBα accumulates in the nucleus of keratinocytes and interacts with histones H2A and H4 at the regulatory region of HOX and IRX genes. Chromatin-bound IκBα modulates Polycomb recruitment and imparts their competence to be activated by TNFα.

A truncated form of IKKα is responsible for specific nuclear IKK activity in colorectal cancer.

Nuclear IKKα regulates gene transcription by phosphorylating specific substrates and has been linked to cancer progression and metastasis. However, the mechanistic connection between tumorigenesis and IKKα activity remains poorly understood. We have now analyzed 288 human colorectal cancer samples and found a significant association between the presence of nuclear IKK and malignancy.